Molecular biology and mechanics of the cardiac interstitium

描述（由申请人提供）：我们的主要目的是证明心壁运动异常，其特征为心外膜中的早期缩短/晚期延长触发、局部炎症、活性氧生成、基质金属蛋白酶（MMP）激活和纤维胶原降解，导致不良心室重塑。在心力衰竭中，继发于左心室（LV）不同步收缩的室壁运动异常降低射血分数并促进重构。类似的变化发生在左心室前壁心外膜起搏的动物模型中，其中不良重构的特征在于起搏部位变薄和后壁肥大。局部应变模式显示早期激活区（前壁）的早期缩短和收缩晚期延长，以及后壁的早期延长和随后的缩短。初步数据表明，前壁起搏产生心外膜白细胞（可能是中性粒细胞）介导的炎症、MMP激活、活性氧生成（ROS）和胶原降解的局部证据。我们认为炎症/损伤的机制是继发于冠状静脉血流模式改变的微血管中粘附分子的局部表达。提出了四个目标。目的1将检验起搏诱导的早期缩短导致冠状静脉中粘附分子的局部表达、白细胞的捕获、ROS的产生、MMP前体的激活和心外膜中纤维状胶原的降解的假设。目的2将检验左心室早期缩短区域表现出异常心外膜收缩期组织体积变化和心外膜小静脉血流模式改变的假设。目的3将在体外和体内验证白细胞产生的ROS在结构上修饰MMP-9原的假设。目的4将检验长期LV室壁运动异常诱导不良腔室重构的假设，其特征在于与早期缩短相关的区域的心外膜壁变薄。将使用各种心脏力学、活体显微镜、蛋白质组学、生物化学和组织学方法。这些研究结果有助于我们理解心力衰竭和左束支分支传导阻滞患者的心室不同步性如何导致不良心室重构和收缩功能丧失。拟议研究的预期结果也可能有助于临床医生优化心脏起搏治疗。 公共卫生相关性拟议的研究解决了一个重要的临床问题，即当心脏不一致收缩时，它如何发展出本质上有害的结构和功能异常。这些异常在心力衰竭患者中常见，我们的观察表明潜在的炎症过程可能解释这些不良变化。

DESCRIPTION (provided by applicant): Our major objective is to demonstrate that heart wall motion abnormalities characterized by early shortening/late lengthening trigger in the epicardium, local inflammation, reactive oxygen species generation, matrix metalloproteinase (MMP) activation and fibrillar collagen degradation leading to adverse chamber remodeling. Wall motion abnormalities secondary to dysynchronous contraction of the left ventricle (LV) as seen in heart failure reduce ejection fraction and promote remodeling. Similar changes occur in animal models of anterior LV wall epicardial pacing whereby adverse remodeling is characterized by thinning at the pacing site and hypertrophy of the posterior wall. Local strain patterns demonstrate early shortening and late systolic lengthening in the early activated areas (anterior wall) and early lengthening and subsequent shortening of the posterior wall. Preliminary data indicates that anterior wall pacing yields localized evidence for epicardial leucocyte (likely neutrophil) mediated inflammation, activation of MMPs, reactive oxygen species generation (ROS) and collagen degradation. We propose that the mechanism responsible for inflammation/injury is the local expression of adhesion molecules in the microvasculature secondary to alterations in coronary venule blood flow patterns. Four aims are proposed. Aim 1 will test the hypothesis that pacing induced early shortening leads to the local expression of adhesion molecules in coronary venules, trapping of leucocytes, generation of ROS, pro-MMP activation and fibrillar collagen degradation in the epicardium. Aim 2 will test the hypothesis that early shortening regions of the LV demonstrate abnormal epicardial systolic tissue volume changes and modified patterns of epicardial venular blood flow. Aim 3 will test the hypothesis that leucocyte generated ROS structurally modifies pro-MMP-9 in vitro and in vivo. Aim 4 will test the hypothesis that long- term LV wall motion abnormalities induce adverse chamber remodeling characterized by epicardial wall thinning in areas associated with early shortening. A variety of cardiac mechanics, intravital microscopy, proteomics, biochemical and histological methods are to be used. Results from the proposed studies should aid in our understanding of how ventricular dysynchrony as seen in patients with heart failure and left bundle branch block leads to the development of adverse chamber remodeling and loss of contractile function. Anticipated outcome from the proposed studies may also aid clinicians in optimizing cardiac resynchronization therapy. PUBLIC HEALTH RELEVANCE The proposed research addresses an important clinical problem related to how, when the heart does not contract in unison it develops structural and functional abnormalities that are detrimental in nature. These abnormalities are frequently seen in patients with heart failure and our observations indicate that an underlying inflammatory process may explain these adverse changes.